tbuckley/cabot-search huggingface dataset:
Potential clinical use of azacitidine and MEK inhibitor combination therapy in PTPN11-mutated juvenile myelomonocytic leukemia
Authors: Santhosh Kumar Pasupuleti, Karen Chao, Baskar Ramdas, Rahul Kanumuri, Lakshmi Reddy Palam, Sheng Liu, Jun Wan, Colleen Annesley, Mignon L. Loh, Elliot Stieglitz, Michael J. Burke, Reuben Kapur
Journal: Molecular Therapy (2023)

Juvenile myelomonocytic leukemia (JMML) is a rare myeloproliferative neoplasm of childhood. The molecular hallmark of JMML is hyperactivation of the Ras/MAPK pathway with the most common cause being mutations in the gene PTPN11, encoding the protein tyrosine phosphatase SHP2. Current strategies for treating JMML include using the hypomethylating agent, 5-azacitidine (5-Aza) or MEK inhibitors trametinib and PD0325901 (PD-901), but none of these are curative as monotherapy. Utilizing an Shp2E76K/+ murine model of JMML, we show that the combination of 5-Aza and PD-901 modulates several hematologic abnormalities often seen in JMML patients, in part by reducing the burden of leukemic hematopoietic stem and progenitor cells (HSC/Ps). The reduced JMML features in drug-treated mice were associated with a decrease in p-MEK and p-ERK levels in Shp2E76K/+ mice treated with the combination of 5-Aza and PD-901. RNA-sequencing analysis revealed a reduction in several RAS and MAPK signaling-related genes. Additionally, a decrease in the expression of genes associated with inflammation and myeloid leukemia was also observed in Shp2E76K/+ mice treated with the combination of the two drugs. Finally, we report two patients with JMML and PTPN11 mutations treated with 5-Aza, trametinib, and chemotherapy who experienced a clinical response because of the combination treatment. Juvenile myelomonocytic leukemia (JMML) is a rare myeloproliferative neoplasm of childhood. The molecular hallmark of JMML is hyperactivation of the Ras/MAPK pathway with the most common cause being mutations in the gene PTPN11, encoding the protein tyrosine phosphatase SHP2. Current strategies for treating JMML include using the hypomethylating agent, 5-azacitidine (5-Aza) or MEK inhibitors trametinib and PD0325901 (PD-901), but none of these are curative as monotherapy. Utilizing an Shp2E76K/+ murine model of JMML, we show that the combination of 5-Aza and PD-901 modulates several hematologic abnormalities often seen in JMML patients, in part by reducing the burden of leukemic hematopoietic stem and progenitor cells (HSC/Ps). The reduced JMML features in drug-treated mice were associated with a decrease in p-MEK and p-ERK levels in Shp2E76K/+ mice treated with the combination of 5-Aza and PD-901. RNA-sequencing analysis revealed a reduction in several RAS and MAPK signaling-related genes. Additionally, a decrease in the expression of genes associated with inflammation and myeloid leukemia was also observed in Shp2E76K/+ mice treated with the combination of the two drugs. Finally, we report two patients with JMML and PTPN11 mutations treated with 5-Aza, trametinib, and chemotherapy who experienced a clinical response because of the combination treatment.
An adipocentric perspective on the development and progression of non-alcoholic fatty liver disease
Authors: Eunyoung Lee, Hannelie Korf, Antonio Vidal-Puig
Journal: Journal of Hepatology (2023)

Alongside the liver, white adipose tissue (WAT) is critical in regulating systemic energy homeostasis. Although each organ has its specialised functions, they must work coordinately to regulate whole-body metabolism. Adipose tissues and the liver are relatively resilient and can adapt to an energy surplus by facilitating triglyceride (TG) storage up to a certain threshold level without significant metabolic disturbances. However, lipid storage in WAT beyond a "personalised" adiposity threshold becomes dysfunctional, leading to metabolic inflexibility, progressive inflammation, and aberrant adipokine secretion. Moreover, the failure of adipose tissue to store and mobilise lipids results in systemic knock-on lipid overload, particularly in the liver. Factors contributing to hepatic lipid overload include lipids released from WAT, dietary fat intake, and enhanced de novo lipogenesis. In contrast, extrahepatic mechanisms counteracting toxic hepatic lipid overload entail coordinated compensation through oxidation of surplus fatty acids in brown adipose tissue and storage of fatty acids as TGs in WAT. Failure of these integrated homeostatic mechanisms leads to quantitative increases and qualitative alterations to the lipidome of the liver. Initially, hepatocytes preferentially accumulate TG species leading to a relatively "benign" non-alcoholic fatty liver. However, with time, inflammatory responses ensue, progressing into more severe conditions such as non-alcoholic steatohepatitis, cirrhosis, and hepatocellular carcinoma, in some individuals (often without an early prognostic clue). Herein, we highlight the pathogenic importance of obesity-induced "adipose tissue failure", resulting in decreased adipose tissue functionality (i.e. fat storage capacity and metabolic flexibility), in the development and progression of NAFL/NASH.
Diagnostic Value of Adding Magnifying Chromoendoscopy to Magnifying Narrow-Band Imaging Endoscopy for Colorectal Polyps
Authors: Tomoaki Matsumura, Alanna Ebigbo, Christoph Römmele, Hiroaki Ikematsu, Hideaki Ishigami, Takuto Suzuki, Hideaki Harada, Tomoyuki Yada, Yusaku Takatori, Manabu Takeuchi, Kenichiro Okimoto, Naoki Akizue, Daisuke Maruoka, Yoshiyasu Kitagawa, Tatsunori Minamide, Tomoyuki Iwaki, Yuji Amano, Keisuke Matsusaka, Kengo Nagashima, Tadateru Maehata, Naohisa Yahagi, Helmut Messmann, Naoya Kato
Journal: Clinical Gastroenterology and Hepatology (2023)
Comparative effectiveness of omalizumab, mepolizumab, and dupilumab in asthma: A target trial emulation
Authors: Ayobami T. Akenroye, Jodi B. Segal, Guohai Zhou, Dinah Foer, Lily Li, G. Caleb Alexander, Corinne A. Keet, John W. Jackson
Journal: Journal of Allergy and Clinical Immunology (2023)

Multiple mAbs are currently approved for the treatment of asthma. However, there is limited evidence on their comparative effectiveness.
Author Correction: Screening for CD19-specific chimaeric antigen receptors with enhanced signalling via a barcoded library of intracellular domains
Authors: Khloe S. Gordon, Taeyoon Kyung, Caleb R. Perez, Patrick V. Holec, Azucena Ramos, Angela Q. Zhang, Yash Agarwal, Yunpeng Liu, Catherine E. Koch, Alina Starchenko, Brian A. Joughin, Douglas A. Lauffenburger, Darrell J. Irvine, Michael T. Hemann, Michael E. Birnbaum
Journal: Nature Biomedical Engineering (2023)
Integration of artificial intelligence in lung cancer: Rise of the machine
Authors: Colton Ladbury, Arya Amini, Ameish Govindarajan, Isa Mambetsariev, Dan J. Raz, Erminia Massarelli, Terence Williams, Andrei Rodin, Ravi Salgia
Journal: Cell Reports Medicine (2023)

The goal of oncology is to provide the longest possible survival outcomes with the therapeutics that are currently available without sacrificing patients' quality of life. In lung cancer, several data points over a patient's diagnostic and treatment course are relevant to optimizing outcomes in the form of precision medicine, and artificial intelligence (AI) provides the opportunity to use available data from molecular information to radiomics, in combination with patient and tumor characteristics, to help clinicians provide individualized care. In doing so, AI can help create models to identify cancer early in diagnosis and deliver tailored therapy on the basis of available information, both at the time of diagnosis and in real time as they are undergoing treatment. The purpose of this review is to summarize the current literature in AI specific to lung cancer and how it applies to the multidisciplinary team taking care of these complex patients.
Autophagy controls mucus secretion from intestinal goblet cells by alleviating ER stress
Authors: Maria Naama, Shahar Telpaz, Aya Awad, Shira Ben-Simon, Sarina Harshuk-Shabso, Sonia Modilevsky, Elad Rubin, Jasmin Sawaed, Lilach Zelik, Mor Zigdon, Nofar Asulin, Sondra Turjeman, Michal Werbner, Supapit Wongkuna, Rachel Feeney, Bjoern O. Schroeder, Abraham Nyska, Meital Nuriel-Ohayon, Shai Bel
Journal: Cell Host & Microbe (2023)

Colonic goblet cells are specialized epithelial cells that secrete mucus to physically separate the host and its microbiota, thus preventing bacterial invasion and inflammation. How goblet cells control the amount of mucus they secrete is unclear. We found that constitutive activation of autophagy in mice via Beclin 1 enables the production of a thicker and less penetrable mucus layer by reducing endoplasmic reticulum (ER) stress. Accordingly, genetically inhibiting Beclin 1-induced autophagy impairs mucus secretion, while pharmacologically alleviating ER stress results in excessive mucus production. This ER-stress-mediated regulation of mucus secretion is microbiota dependent and requires the Crohn's-disease-risk gene Nod2. Overproduction of mucus alters the gut microbiome, specifically expanding mucus-utilizing bacteria, such as Akkermansia muciniphila, and protects against chemical and microbial-driven intestinal inflammation. Thus, ER stress is a cell-intrinsic switch that limits mucus secretion, whereas autophagy maintains intestinal homeostasis by relieving ER stress.
Oxidative phosphorylation selectively orchestrates tissue macrophage homeostasis
Authors: Stefanie K Wculek, Ignacio Heras-Murillo, Annalaura Mastrangelo, Diego Mañanes, Miguel Galán, Verónica Miguel, Andrea Curtabbi, Coral Barbas, Navdeep S Chandel, José Antonio Enríquez, Santiago Lamas, David Sancho
Journal: Immunity (2023)
Mouse population genetics phenocopies heterogeneity of human Chd8 haploinsufficiency
Authors: Manal Tabbaa, Allison Knoll, Pat Levitt
Journal: Neuron (2023)

Preclinical models of neurodevelopmental disorders typically use single inbred mouse strains, which fail to capture the genetic diversity and symptom heterogeneity that is common clinically. We tested whether modeling genetic background diversity in mouse genetic reference panels would recapitulate population and individual differences in responses to a syndromic mutation in the high-confidence autism risk gene, CHD8. We measured clinically relevant phenotypes in >1,000 mice from 33 strains, including brain and body weights and cognition, activity, anxiety, and social behaviors, using 5 behavioral assays: cued fear conditioning, open field tests in dark and bright light, direct social interaction, and social dominance. Trait disruptions mimicked those seen clinically, with robust strain and sex differences. Some strains exhibited large effect-size trait disruptions, sometimes in opposite directions, and-remarkably-others expressed resilience. Therefore, systematically introducing genetic diversity into models of neurodevelopmental disorders provides a better framework for discovering individual differences in symptom etiologies.
Towards precision medicine based on a continuous deep learning optimization and ensemble approach
Authors: Jian Li, Linyuan Jin, Zhiyuan Wang, Qinghai Peng, Yueai Wang, Jia Luo, Jiawei Zhou, Yingying Cao, Yanfen Zhang, Min Zhang, Yuewen Qiu, Qiang Hu, Liyun Chen, Xiaoyu Yu, Xiaohui Zhou, Qiong Li, Shu Zhou, Si Huang, Dan Luo, Xingxing Mao, Yi Yu, Xiaomeng Yang, Chiling Pan, Hongxin Li, Jingchao Wang, Jieke Liao
Journal: npj Digital Medicine (2023)

We developed a continuous learning system (CLS) based on deep learning and optimization and ensemble approach, and conducted a retrospective data simulated prospective study using ultrasound images of breast masses for precise diagnoses. We extracted 629 breast masses and 2235 images from 561 cases in the institution to train the model in six stages to diagnose benign and malignant tumors, pathological types, and diseases. We randomly selected 180 out of 3098 cases from two external institutions. The CLS was tested with seven independent datasets and compared with 21 physicians, and the system's diagnostic ability exceeded 20 physicians by training stage six. The optimal integrated method we developed is expected accurately diagnose breast masses. This method can also be extended to the intelligent diagnosis of masses in other organs. Overall, our findings have potential value in further promoting the application of AI diagnosis in precision medicine.
Retraction Note: Facial expressions can detect Parkinson’s disease: preliminary evidence from videos collected online
Authors: Mohammad Rafayet Ali, Taylor Myers, Ellen Wagner, Harshil Ratnu, E. Ray Dorsey, Ehsan Hoque
Journal: npj Digital Medicine (2023)

was performed on an inaccurate use of a data pre-processing tool, which resulted in an information leak from train to test samples.This has resulted in incorrect classification metrics.However, the statistical differences between features of PD and non-PD populations indicate that this is still an area worthy of further investigation.
The use of kiosks to improve triage efficiency in the emergency department
Authors: Michael Jose Joseph, Matthew Summerscales, Saieesha Yogesan, Anthony Bell, Michele Genevieve, Yogesan Kanagasingam
Journal: npj Digital Medicine (2023)

Triage is a system used to prioritise patients as they enter the emergency department (ED) based on their need for urgent care. In recent decades, EDs have becoming increasingly overcrowded, leading to longer pre-triage waiting times for patients. E-triage interventions like kiosks have been proposed as a solution to overcrowding. We conducted a literature review into the effectiveness of kiosks in improving triage efficiency. After rigorously searching five biomedical databases and screening candidate articles in Endnote, we identified nine papers pertaining to the introduction of kiosks in emergency departments. Six articles had positive findings-with E-triage interventions improving some aspect of the triage process-such as reducing pre-triage times. Conversely, only three articles reported negative findings, such as low uptake. Consequently, EDs should consider introducing kiosks to complement the current nurse-led triage process and thereby promote better patient outcomes.
Plasma extracellular vesicle messenger RNA profiling identifies prognostic EV signature for non-invasive risk stratification for survival prediction of patients with pancreatic ductal adenocarcinoma
Authors: Yi Han, Pascal Drobisch, Alexander Krüger, Doreen William, Konrad Grützmann, Lukas Böthig, Heike Polster, Lena Seifert, Adrian M. Seifert, Marius Distler, Mathieu Pecqueux, Carina Riediger, Verena Plodeck, Heiner Nebelung, Georg F. Weber, Christian Pilarsky, Ulf Kahlert, Ulf Hinz, Susanne Roth, Thilo Hackert, Jürgen Weitz, Fang Cheng Wong, Christoph Kahlert
Journal: Journal of Hematology & Oncology (2023)

The prognosis of pancreatic ductal adenocarcinoma (PDAC) is one of the most dismal of all cancers and the median survival of PDAC patients is only 6-8 months after diagnosis. While decades of research effort have been focused on early diagnosis and understanding of molecular mechanisms, few clinically useful markers have been universally applied. To improve the treatment and management of PDAC, it is equally relevant to identify prognostic factors for optimal therapeutic decision-making and patient survival. Compelling evidence have suggested the potential use of extracellular vesicles (EVs) as non-invasive biomarkers for PDAC. The aim of this study was thus to identify non-invasive plasma-based EV biomarkers for the prediction of PDAC patient survival after surgery.Plasma EVs were isolated from a total of 258 PDAC patients divided into three independent cohorts (discovery, training and validation). RNA sequencing was first employed to identify differentially-expressed EV mRNA candidates from the discovery cohort (n = 65) by DESeq2 tool. The candidates were tested in a training cohort (n = 91) by digital droplet polymerase chain reaction (ddPCR). Cox regression models and Kaplan-Meier analyses were used to build an EV signature which was subsequently validated on a multicenter cohort (n = 83) by ddPCR.Transcriptomic profiling of plasma EVs revealed differentially-expressed mRNAs between long-term and short-term PDAC survivors, which led to 10 of the top-ranked candidate EV mRNAs being tested on an independent training cohort with ddPCR. The results of ddPCR enabled an establishment of a novel prognostic EV mRNA signature consisting of PPP1R12A, SCN7A and SGCD for risk stratification of PDAC patients. Based on the EV mRNA signature, PDAC patients with high risk displayed reduced overall survival (OS) rates compared to those with low risk in the training cohort (p = 0.014), which was successfully validated on another independent cohort (p = 0.024). Interestingly, the combination of our signature and tumour stage yielded a superior prognostic performance (p = 0.008) over the signature (p = 0.022) or tumour stage (p = 0.016) alone. It is noteworthy that the EV mRNA signature was demonstrated to be an independent unfavourable predictor for PDAC prognosis.This study provides a novel and non-invasive prognostic EV mRNA signature for risk stratification and survival prediction of PDAC patients.
Platelet Adherent Eosinophils Drive ILC2 Expansion
Authors: Hiroaki Hayashi, Jun Nagai, Tao Liu, Chunli Feng, Kendall Zaleski, Junrui Lin, Yumi Tani, Airi Nishida, Kinan Alhallak, Barbara Balestrieri, Joshua Boyce
Journal: Journal of Allergy and Clinical Immunology (2023)
The Network of Epithelial Cells and ILC2s Involving Acetylcholine and Muscarinic Receptors Promote Type 2 Immune Responses to Inhaled Allergen
Authors: Ryusuke Hayashi, Koji Iijima, Takao Kobayashi, Mayumi Matsunaga, Rinna Tei, Hirohito Kita
Journal: Journal of Allergy and Clinical Immunology (2023)
MICRODELETION CHROMOSOME SYNDROME - 3,7 MB INTERSTITIAL DELETION OF CHROMOSOME 15Q24.1Q24.3 ASSOCIATED TO IMMUNODEFICIENCY
Authors: Laiane Bezerra Fernandes Capistrano, Daniela Albarello, Allexia Lacerda Soares, Carolina TELO GEHLEN, Arnaldo Porto Neto
Journal: Journal of Allergy and Clinical Immunology (2023)
Differences In Therapeutic Efficacy Between Pressurized Metered-dose Inhaler And Dry Powder Inhaler For Asthma Patients With Small Airway Dysfunction
Authors: Susumu Fukahori, Seong Cho, Yasushi Obase, Chizu Fukushima, Hiroshi Mukae, Richard Lockey
Journal: Journal of Allergy and Clinical Immunology (2023)
Discrete T-Cell and Inflammatory Profiles in the Blood Define Pulmonary Phenotypes After COVID-19 Illness.
Authors: Glenda Canderan, Lyndsey Muehling, Alexandra Kadl, Jeffrey Sturek, Catherine Bonham, Deborah Murphy, Sierra Barone, Claire Cross, In Su Cheon, Jie Sun, None Jonathan irish, Judith Woodfolk
Journal: Journal of Allergy and Clinical Immunology (2023)
Severe Combined Immunodeficiency (SCID) Patient and Families Report Significant Financial Burden
Authors: Kelsey Ige, Kathy Nguyen, David Buchbinder, Manish Butte, Cathleen Collins, Morton Cowan, Victoria Dimitriades, Sean McGhee, Ami Shah, Jennifer Puck, Heather Smith, Xin-Hua Chen, Linda Franck, Morna Dorsey
Journal: Journal of Allergy and Clinical Immunology (2023)
Reproduction of HLA-A*32:01 and other genetic and ecological factors associated with Vancomycin Drug Reaction With Eosinophilia And Systemic Symptoms in An Electronic Health Record-Based Study
Authors: Matthew Krantz, Jun Qian, Cosmin Bejan, Siwei Zhang, Yoamin Xu, Wei-Qi Wei, Brian Yoon, Jason Trubiano, Elizabeth Phillips
Journal: Journal of Allergy and Clinical Immunology (2023)
Atopic march Eosinophil-Derived Neurotoxin levels and the onset of allergic airway disease in preschool children
Authors: Chang-Keun Kim, Yoshihide Terashi, Zak Callaway, Eunmi Kwon, Shinya Yoshihara, Masaya Kato, Shigemi Yoshihara
Journal: Journal of Allergy and Clinical Immunology (2023)
Macrophage and Neutrophil Dysregulation are Associated with Persistent COVID-19-induced Olfactory Dysfunction
Authors: Dante Minichetti, Amelia Boyd, Jonathan Hacker, Caitlin Wong, Evan Lemire, Kathleen Buchheit, Stella Lee, Rachel Roditi, Adam Haber, Tanya Laidlaw
Journal: Journal of Allergy and Clinical Immunology (2023)

While disruption of smell (dysosmia) and taste (dysgeusia) are associated with upper respiratory infections and chronic rhinosinusitis, their high frequency and severity is unique to COVID-19. We aimed to determine the characteristics of persistent dysosmia and dysgeusia after COVID-19 and define the mechanistic correlates. Study subjects with persistent olfactory or taste distortions (n=42) after COVID-19 and controls with normal smell and no history of COVID-19 (n=16) at the time of enrollment were recruited. All subjects underwent objective evaluations using validated assessment tools for smell (UPSIT) and taste (B-WETT) acuity. Cells for RNA sequencing and nasal fluid for mediator analysis were collected with self-administered Floqswabs and nasosorption strips. Among study subjects with persistent post-COVID-19 (average 6, range 2-18 months) sensory disruption, both UPSIT(26±7) and BWETT(17±4) were significantly (p<0.01) reduced compared with controls (UPSIT 33±2, BWETT 20±4). COVID19-induced sensory distortions cluster into four phenotypes: subjective dysosmia (UPSIT≥26, B-WETT≥17), objective dysosmia (UPSIT≤25, B-WETT≥17), dysgeusia (UPSIT≥26, B-WETT≤16), or combined dysosmia and dysgeusia (UPSIT≤25, B-WETT≤16). RNAseq analysis revealed an increase of macrophage and neutrophil-associated transcriptional signatures in subjects with both dysosmia phenotypes but not in those with dysgeusia. Conversely, the nasal hydroxyoctadecadienoic acid metabolites (9-HODE and 13-HODE) and the lipokine 12,13di-HOME were elevated in subjects with dysgeusia and negatively correlated with BWETT (9-HODE r=-0.45, p=0.009, 13-HODE r=-0.46, p=0.008, 12,13d-HOME r=-0.38, p=0.027). An imprint of dysregulated macrophage and neutrophil mediated-immune response emerges from transcriptional data of persistent post-COVID19 dysosmia. The distinct dysgeusia phenotypes are associated with eicosanoid dysregulation. COVID19-induced sensory distortion is likely a multifactorial syndrome with distinct phenotypes.
Is There Any Relationship Between Chronic Urticaria, Its Severity and Alexithymia?
Authors: Luis Miguel Escalante Fiallos, Ivan Cherrez Ojeda, Simon Thomsen, Ana Giménez-Arnau, Jennifer Astrup Sørensen, Kiran Godse, Carole Guillet, Astrid Karolina Maldonado Apolo, Gonzalo Chorzepa, Blanca Morfin-Maciel, Jose Ignacio Larco Sousa, Erika De Arruda Chaves, Abhishek De, Daria Fomina, Anant Patil, Roberta Jardim Criado, Luis Felipe Ensina, Solange Valle, Rosana Agondi, Herberto Chong Neto, Nelson Rosario, German Dario Ramon, Marco Faytong-Haro, Isabel Ogueta, Ivan Tinoco Moran, Jaime Cárdenas, Mariana Tinoco Chabla, Sandy Aguilar Gavilanes, Victor Estuardo Farinango Salazar, Silvio Duran Huacon, Pablo Maldonado Donoso, Nelson Muñoz, Johnny Gallardo Gallardo, Damelis Martinez Letterni, Karla Robles-Velasco
Journal: Journal of Allergy and Clinical Immunology (2023)
Down-Modulation of Cockroach (CR) Allergen-specific Th2 Cell Responses Following Subcutaneous German Cockroach Allergen Immunotherapy (SCIT)
Authors: Ricardo Da Silva Antunes, April Frazier, Anna Pomés, Augustin Calatroni, Robert Wood, George O'Connor, Jacqueline Pongracic, Gurjit Khurana Hershey, Carolyn Kercsmar, Michelle Gill, Andrew Liu, Edward Zoratti, Meyer Kattan, Paula Busse, Leonard Bacharier, Stephen Teach, Stephen Teach, Stephen Teach, Lisa Wheatley, Alkis Togias, William Busse, Daniel Jackson, Alessandro Sette, Alessandro Sette
Journal: Journal of Allergy and Clinical Immunology (2023)
Subcutaneous immunotherapy with mannan-conjugated birch pollen allergens shows long-term effects already after 2 years of treatment by inducing a significant immune response in birch pollen allergic patients
Authors: Esther Raskopf, Laura England, Hacer Sahin, Christoph Zeyen, Lea Decker, Friederike Hüffmeier, Elena Xenofontos, Miguel Casanovas, José Subiza, Silke Allekotte, Mandy Cuevas, Ralph Mosges
Journal: Journal of Allergy and Clinical Immunology (2023)